Real-World Cervical Cancer Screening Uptake and Predictors of Visual Inspection With Acetic Acid Positivity Among Women Living With HIV in Care Programs in Western Kenya.

PURPOSE: To achieve the WHO cervical cancer elimination targets, countries globally must achieve 70% cervical cancer screening (CCS) coverage. We evaluated CCS uptake and predictors of screening positive at two public HIV care programs in western Kenya. METHODS: From October 2007 to February 2019, data from the Family AIDS Care and Education Services (FACES) and Academic Model Providing Access to Healthcare (AMPATH) programs in western Kenya were analyzed. The study population included women age 18-65 years enrolled in HIV care. Screening uptake was calculated annually and overall, determining the proportion of eligible women screened. Multivariate logistic regression assessed predictors of positive screening outcomes. RESULTS: There were 57,298 women living with HIV (WLWHIV) eligible for CCS across both programs during the study period. The mean age was 31.4 years (IQR, 25.9-37.8), and 39% were on antiretroviral therapy (ART) at the first CCS-eligible visit. Of all eligible women, 29.4% (95% CI, 29.1 to 29.8) underwent CCS during the study period, 27.0% (95% CI, 26.5 to 27.4) in the AMPATH program, and 35.6% (95% CI, 34.9 to 36.4) in the FACES program. Annual screening uptake varied greatly in both programs, with coverage as low as 1% of eligible WLWHIV during specific years. Age at first screening, CD4 count within 90 days of screening, current use of ART, and program (AMPATH v FACES) were each statistically significant predictors of positive screening. CONCLUSION: CCS uptake at two large HIV care programs in Kenya fell short of the WHO's 70% screening target. Screening rates varied significantly on the basis of the availability of funding specific to CCS, reflecting the limitations of vertical funding programs.

Association of plasma aflatoxin with persistent detection of oncogenic human papillomaviruses in cervical samples from Kenyan women enrolled in a longitudinal study.

BACKGROUND: Cervical cancer is caused by oncogenic human papillomaviruses (HR-HPV) and is common among Kenyan women. Identification of factors that increase HR-HPV persistence is critically important. Kenyan women exposed to aflatoxin have an increased risk of HR-HPV detection in cervical specimens. This analysis was performed to examine associations between aflatoxin and HR-HPV persistence. METHODS: Kenyan women were enrolled in a prospective study. The analytical cohort for this analysis included 67 HIV-uninfected women (mean age 34 years) who completed at least two of three annual study visits and had an available blood sample. Plasma aflatoxin was detected using ultra-high pressure liquid chromatography (UHPLC)-isotope dilution mass spectrometry. Annual cervical swabs were tested for HPV (Roche Linear Array). Ordinal logistic regression models were fitted to examine associations of aflatoxin and HPV persistence. RESULTS: Aflatoxin was detected in 59.7% of women and was associated with higher risk of persistent detection of any HPV type (OR = 3.03, 95%CI = 1.08-8.55, P = 0.036), HR-HPV types (OR = 3.63, 95%CI = 1.30-10.13, P = 0.014), and HR-HPV types not included in the 9-valent HPV vaccine (OR = 4.46, 95%CI = 1.13-17.58, P = 0.032). CONCLUSIONS: Aflatoxin detection was associated with increased risk of HR-HPV persistence in Kenyan women. Further studies, including mechanistic studies are needed to determine if aflatoxin synergistically interacts with HR-HPV to increase cervical cancer risk.

Association of Plasma Aflatoxin With Persistent Detection of Oncogenic Human Papillomaviruses in Cervical Samples From Kenyan Women Enrolled in a Longitudinal Study.

Background Cervical cancer is common among Kenyan women and is caused by oncogenic human papillomaviruses (HR-HPV). Identification of factors that increase HR-HPV persistence is critically important. Kenyan women exposed to aflatoxin have an increased risk of cervical HR-HPV detection. This analysis was performed to examine associations between aflatoxin and HR-HPV persistence. Methods Kenyan women were enrolled in a prospective study. The analytical cohort for this analysis included 67 HIV-uninfected women (mean age 34 years) who completed at least two of three annual study visits and had an available blood sample. Plasma aflatoxin was detected using ultra-high pressure liquid chromatography (UHPLC)-isotope dilution mass spectrometry. Annual cervical swabs were tested for HPV (Roche Linear Array). Ordinal logistic regression models were fitted to examine associations of aflatoxin and HPV persistence. Results Aflatoxin was detected in 59.7% of women and was associated with higher risk of persistent detection of any HPV type (OR = 3.03, 95%CI = 1.08-8.55, P = 0.036), HR-HPV types (OR = 3.63, 95%CI = 1.30-10.13, P = 0.014), and HR-HPV types not included in the 9-valent HPV vaccine (OR = 4.46, 95%CI = 1.13-17.58, P = 0.032). Conclusions Aflatoxin detection was associated with increased risk of HR-HPV persistence in Kenyan women. Further studies are needed to determine if aflatoxin synergistically interacts with HR-HPV to increase cervical cancer risk.

A community-based approach to cervical cancer prevention in western Kenya: An AMPATH feasibility project.

Objectives: Centralized programs have been ineffective in reducing the burden of cervical cancer among Kenyan women. A community-based pilot study was initiated to screen Kenyan women for cervical cancer and to vaccinate their children against human papillomavirus (HPV). Methods: Women were educated about cervical cancer prevention at community meetings. Women then provided self-collected vaginal swabs for oncogenic HPV testing using the Roche Cobas Assay. All women were then referred to the local clinic for Visual Inspection with Acetic Acid (VIA). Women were offered the quadrivalent HPV vaccine for their children if and when it became available for the study. Results: Women in western Kenya were invited to participate in community meetings. A total of 200 women were enrolled: 151 (75.5%) were HIV-uninfected and 49 (24.5%) were HIV-infected; the median age for all women was 42 years. High-risk (HR)-HPV types were detected in 49 of swabs from all 200 participants (24.5%) including 20.5% of HIV-uninfected women and 36.7% of HIV-infected women (P = .022). VIA was performed on 198 women: 192 had normal examinations and six had abnormal examinations. Five cervical biopsies revealed two cases of CIN 2 and one CIN 3. Although all mothers were willing to have their children (N = 432) vaccinated, the HPV vaccine could not be delivered to Kenya during the study period. Conclusions: Kenyan women were willing to attend community meetings to learn about prevention of cervical cancer, to provide self-collected vaginal swabs for HPV testing, to travel to the Webuye Clinic for VIA following the collection of swabs, and to have their children vaccinated against HPV. HR-HPV was prevalent, especially in HIV-infected women. As a result of this pilot study, this community-based strategy to prevent cervical cancer will be continued in western Kenya.

Genetic diversity in L1 ORF of human papillomavirus in women with cervical cancer with and without human immunodeficiency virus in Botswana and Kenya.

BACKGROUND: The variation of human papillomavirus (HPV) genotypes shapes the risks of cervical cancer and these variations are not well defined in Africa. Nucleotide changes within the L1 gene, nucleotide variability, and phylogeny were explored in relation to HIV in samples from Botswana and Kenya. METHODS: A total of 98 HPV-positive cervical samples were sequenced to identify different HPV variants. Phylogenetic inferences were used to determine HPV genotypes and investigate the clustering of sequences between women living with HIV (WLWHIV) and -women not living with HIV (WNLWHIV). RESULTS: Out of 98 generated sequences, 83.7% (82/98) participants had high-risk (HR) HPV genotypes while 16.3% (16/98) had low-risk (LR) HPV genotypes. Among participants with HR-HPV genotypes, 47.6% (39/82) were coinfected with HIV. The prevalence of HR-HPV genotypes was statistically higher in the Botswana population compared to Kenya (p-value < 0.001). Multiple amino acid mutations were identified in both countries. Genetic diversity differed considerably among WLWHIV and WNLWHIV. The mean pairwise distances between HPV-16 between HIV and HIV/HPV as well as for HPV-18 were statistically significant. Six (6) new deleterious mutations were identified in the HPV genotypes based on the sequencing of the L1 region, HPV-16 (L441P, S343P), HPV-18 (S424P), HPV-45 (Q366H, Y365F), and HPV-84 (F458L). The majority of the patients with these mutations were co-infected with HIV. CONCLUSIONS: Genomic diversity and different genomic variants of HPV sequences were demonstrated. Candidate novel mutations within the L1 gene were identified in both countries which can be further investigated using functional assays.

Longer duration of anti-retroviral therapy is associated with decreased risk of human papillomaviruses detection in Kenyan women living with HIV.

OBJECTIVE: A longitudinal study was conducted among women living with HIV in Kenya to determine if duration of anti-retroviral (ART) usage altered detection and persistence of oncogenic (high-risk) human papillomaviruses (HR-HPV). METHODS: Women living with HIV without cervical dysplasia were enrolled at a cervical cancer screening clinic. Three cervical swabs, HIV viral loads, and CD4 cell counts were obtained at enrollment and at two annual visits. HPV genotyping was performed on swabs (Roche Linear Array). Linear regression models assessed effects of ART duration on HR-HPV detection and persistence. RESULTS: Seventy-seven women, median age 38 years, completed three study visits and were included in the analysis. The mean time from HIV diagnosis to enrollment was 9.6 years (SD 3.9 years). The mean ART duration was 6.2 years (SD 3.1 years). Most women had undetectable HIV viral loads and CD4 cell counts above 500 cells/L. Each additional year of ART use reduced the likelihood of detection of HR-HPV by 10-15% and persistent detection of A9 HR-HPV by 20%. CONCLUSION: Among Kenyan women living with HIV, longer duration of ART use was associated with significantly reduced risk of all detection and persistent detection of HR-HPV.

Novel biomarkers with promising benefits for diagnosis of cervical neoplasia: a systematic review.

BACKGROUND: Cervical cancer screening is slowly transitioning from Pappanicolaou cytologic screening to primary Visual Inspection with Acetic Acid (VIA) or HPV testing as an effort to enhance early detection and treatment. However, an effective triage tests needed to decide who among the VIA or HPV positive women should receive further diagnostic evaluation to avoid unnecessary colposcopy referrals is still lacking. Evidence from experimental studies have shown potential usefulness of Squamous Cell Carcinoma Antigen (SCC Ag), Macrophage Colony Stimulating Factor (M-CSF), Vascular Endothelial Growth Factor (VEGF), MicroRNA, p16INKa / ki-67, HPV E6/E7/mRNA, and DNA methylation biomarkers in detecting premalignant cervical neoplasia. Given the variation in performance, and scanty review studies in this field, this systematic review described the diagnostic performance of some selected assays to detect high-grade cervical intraepithelial neoplasia (CIN2+) with histology as gold standard. METHODS: We systematically searched articles published in English between 2012 and 2020 using key words from PubMed/Medline and SCOPUS with two reviewers assessing study eligibility, and risk of bias. We performed a descriptive presentation of the performance of each of the selected assays for the detection of CIN2 + . RESULTS: Out of 298 citations retrieved, 58 articles were included. Participants with cervical histology yielded CIN2+ proportion range of 13.7-88.4%. The diagnostic performance of the assays to detect CIN2+ was; 1) SCC-Ag: range sensitivity of 78.6-81.2%, specificity 74-100%. 2) M-CSF: sensitivity of 68-87.7%, specificity 64.7-94% 3) VEGF: sensitivity of 56-83.5%, specificity 74.6-96%. 4) MicroRNA: sensitivity of 52.9-67.3%, specificity 76.4-94.4%. 5) p16INKa / ki-67: sensitivity of 50-100%, specificity 39-90.4%. 6) HPV E6/E7/mRNA: sensitivity of 65-100%, specificity 42.7-90.2%, and 7) DNA methylation: sensitivity of 59.7-92.9%, specificity 67-98%. CONCLUSION: Overall, the reported test performance and the receiving operating characteristics curves implies that implementation of p16ink4a/ki-67 assay as a triage for HPV positive women to be used at one visit with subsequent cryotherapy treatment is feasible. For the rest of assays, more robust clinical translation studies with larger consecutive cohorts of women participants is recommended.

Persistence of oncogenic and non-oncogenic human papillomavirus is associated with human immunodeficiency virus infection in Kenyan women.

OBJECTIVES: Cervical cancer is caused by persistent infection with oncogenic, or "high-risk" types of human papillomaviruses, and is the most common malignancy in Kenyan women. A longitudinal study was initiated to investigate factors associated with persistent human papillomavirus detection among HIV-infected and HIV-uninfected Kenyan women without evidence of cervical dysplasia. METHODS: Demographic/behavioral data and cervical swabs were collected from HIV-uninfected women (n = 82) and HIV-infected women (n = 101) at enrollment and annually for 2 years. Human papillomavirus typing was performed on swabs (Roche Linear Array). Logistic regression models of human papillomavirus persistence were adjusted for demographic and behavioral characteristics. RESULTS: HIV-infected women were older and less likely to be married and to own a home and had more lifetime sexual partners than HIV-uninfected women. All HIV-infected women were receiving anti-retroviral therapy at enrollment and had satisfactory CD4 cell counts and HIV viral loads. One- and two-year persistent human papillomavirus detection was significantly associated with HIV infection for any human papillomavirus, high-risk human papillomavirus, International Agency for the Research on Cancer-classified high-risk human papillomavirus, and non-oncogenic "low-risk" human papillomavirus. CONCLUSION: Persistent detection of oncogenic and non-oncogenic human papillomavirus was strongly associated with HIV infection in Kenyan women with re-constituted immune systems based on satisfactory CD4 cell counts. In addition to HIV infection, factors associated with an increased risk of human papillomavirus persistence included a higher number of lifetime sex partners. Factors associated with decreased risk of human papillomavirus persistence included older age and being married. Further studies are needed to identify the immunological defects in HIV-infected women that allow human papillomavirus persistence, even in women receiving effective anti-retroviral therapy. Further studies are also needed to determine the significance of low-risk human papillomavirus persistence in HIV-infected women.

Loop Electrosurgical Excision Procedure Treats Cervical Intraepithelial Neoplasia 2/3 Among HIV- and HIV+ Women in Kenya.

OBJECTIVE: The aim of the study was to compare loop electrosurgical excision procedure (LEEP) as treatment for cervical intraepithelial neoplasia (CIN) 2/3 in HIV- versus HIV+ women. MATERIALS AND METHODS: Seventy-five HIV- and 75 HIV+ women at 6 months or more after LEEP for CIN 2/3 were enrolled between September 2013 and November 2014 in this prospective cohort study at the cervical cancer screening clinic in Eldoret, Kenya. Visual inspection with acetic acid (VIA), followed by cervical cytology with conventional cytology, was performed on all women. Women with positive VIA or abnormal cervical cytology underwent colposcopy/biopsy. Lesion progression, persistence, and regression were assessed to quantify the efficacy of LEEP. RESULTS: Post-loop electrosurgical excision procedure screening test showed both a negative VIA and normal cervical cytology in 64 (85%) of HIV- and 57 (77%) HIV+ women (risk difference = 8.3%, CI = -4.2% to 21%, p = .20). Eleven (15%) HIV- and 17 (23%) HIV+ (p = .20) women had positive VIA, abnormal cervical cytology, or both and were referred for colposcopy/biopsy. Twenty-one (8 HIV-, 13 HIV+) women were biopsied. Of the 8 HIV- women, 4 (50%) had CIN lesions that regressed, 3 (38.0%) persisted, and 1 (12%) progressed to invasive cancer after LEEP. Of the 13 HIV+ women, 6 (46%) had CIN lesions that regressed, 7 (54%) had CIN lesions that persisted, and no HIV+ women had CIN lesions that progressed after LEEP. There was no difference in estimated efficacies of LEEP for HIV- and HIV+ women (92.7% versus 89.4%, risk difference = 3.3%, CI = -4.8% to 15.3%, p = .85). CONCLUSIONS: Loop electrosurgical excision procedure for CIN 2/3 is effective treatment for HIV- and HIV+ women in low-resource settings. Future efforts should improve follow-up after treatment.

Detection and Concentration of Plasma Aflatoxin is Associated with Detection of Oncogenic Human Papillomavirus in Kenyan Women.

BACKGROUND: Cervical cancer is common in Kenyan women. Cofactors in addition to infection with oncogenic human papillomavirus (HPV) are likely to be important in causing cervical cancer, as only a small percentage of HPV-infected women will develop this malignancy. Kenyan women are exposed to dietary aflatoxin, a potent carcinogen and immunosuppressive agent, which may be such a co-factor. METHODS: Demographics, behavioral data, plasma, and cervical swabs were collected from 88 HIV-uninfected Kenyan women without cervical dysplasia. HPV detection was compared between women with or without plasma AFB1-lys and evaluated in relation to AFB1-lys concentration. RESULTS: Valid HPV testing results were available for 86 women (mean age 34.0 years); 49 women (57.0%) had AFB1-lys detected and 37 (43.0%) had none. AFB1-lys detection was not associated with age, being married, having more than secondary school education, home ownership, living at a walking distance to health care ≥60 minutes, number of lifetime sex partners, or age of first sex. AFB1-lys detection and plasma concentrations were associated with detection of oncogenic HPV types. CONCLUSIONS: AFB1-lys-positivity and higher plasma AFB1-lys concentrations were associated with higher risk of oncogenic HPV detection in cervical samples from Kenya women. Further studies are needed to determine if aflatoxin interacts with HPV in a synergistic manner to increase the risk of cervical cancer.

Levonorgestrel only emergency contraceptive use and risk of ectopic pregnancy in Eldoret Kenya: a case-control study.

INTRODUCTION: ectopic pregnancy is one of the causes of maternal morbidity and mortality in sub-Saharan Africa. Levonorgestrel (LNG) only emergency contraceptive pill is a well-established emergency contraceptive pill that is administered within 72 hours after unprotected intercourse. This study aimed at determining whether or not there is a significant association between levonorgestrel emergency contraceptive use and the occurrence of ectopic pregnancy. METHODS: case-control (1:3) study among 79 women with ectopic pregnancy (cases) matched against 237 women without (controls) at Moi Teaching and Referral Hospital in Eldoret, Kenya; Sociodemographic and clinical data were collected using a questionnaire. Association between ectopic pregnancy and LNG-EC was assessed using Pearson chi-square test. The relationship between outcome and exposure (while adjusting for confounders) was assessed using logistic regression model. RESULTS: The mean age was 27.15 years. Both cases and controls were similar by age (p = 0.990), educational level (p = 0.850), marital status (p = 0.559), employment status (p = 0.186) and parity (p = 0.999). Seventy-eight (24.7%) participants had a history of miscarriage. A higher proportion of the cases had history of using LNG-EC compared to the controls (32.9% vs. 7.2%, p < 0.001). The use of LNG-EC portended more than nine times increased odds of ectopic pregnancy compared to other contraceptive methods {OR = 9.34 (95% CI: 3.9 - 16.0)}. CONCLUSION: levonorgestrel only emergency contraceptive use was associated with ectopic pregnancy. One of the limitations of this study is that we could not control for all confounders of ectopic pregnancy.

Invasive cervical cancers in the United States, Botswana and Kenya: HPV type distribution and health policy implications.

BACKGROUND: More deaths occur in African women from invasive cervical cancer (ICC) than from any other malignancy. ICC is caused by infection with oncogenic types of human papillomavirus (HPV). Co-infection with the human immunodeficiency virus (HIV) accelerates the natural history of ICC, and may influence the HPV type distribution. Because HPV vaccines are available, this malignancy is theoretically preventable, but the vaccines are largely type-specific in protection against infection. Data on specific HPV types causing ICC in African women is limited, and many studies utilized swab samples rather than actual cancer tissue. A previous study using archived, ICC tissue from women in Botswana identified an unusual HPV type distribution. A similar study was therefore performed in a second sub-Saharan country to provide additional information on the HPV type distribution in ICC. METHODS: Archived, formalin-fixed, paraffin-embedded ICCs were acquired from women in the United States, Kenya, or Botswana. DNA was extracted and HPV genotyping performed by Roche Linear Array. HIV sequences were identified in ICCs by PCR. RESULTS: HPV types 16 or 18 (HPV 16/18) were identified in 93.5 % of HPV-positive ICCs from the U.S., 93.8 % from Kenya, and 61.8 % from Botswana (p < 0.0001). Non-HPV 16/18 types were detected in 10.9 % of HPV-positive cancers from the U.S., 17.2 % from Kenya, and 47.8 % from Botswana (p < 0.0001). HIV was detected in 2.2, 31.5, and 32.4 % from ICCs from the U.S., Kenya, or Botswana, respectively (p = 0.0002). The distribution of HPV types was not significantly different between HIVinfected or HIV-uninfected women. The percentages of ICCs theoretically covered by the bivalent/quadrivalent HPV vaccines were 93.5, 93.9, and 61.8 % from the U.S., Kenya and Botswana, respectively, and increased to 100, 98, and 77.8 % for the nanovalent vaccine. CONCLUSIONS: HPV 16/18 caused most ICCs from the U.S. and western Kenya. Fewer ICCs contained HPV 16/18 in Botswana. HIV co-infection did not influence the HPV type distribution in ICCs from African women from the two countries. Available HPV vaccines should provide protection against most ICCs in the U.S. and Kenya. The recently developed nanovalent vaccine may be more suitable for countries where non-HPV 16/18 types are frequently detected in ICC.